A transgenic mouse model with a known and specific inborn genetic impair- ment of the type II glucocorticoid receptor function is used to study the impact of the resulting deficient glucocorticoid negative feedback on the response to stress and anxiogenic stimuli, and on the sensitization to stress at both the neurochemical and behavioral levels. We are also studying the modulation of target mRNA levels, particularly of the glucocorticoid receptor, 5-HT2a and 5-HT1a receptors, CRF receptor, CRF, and NPY by various pharmacological treatments in conjunction with their impact on the behavior of these transgenic mice. We have determined that these animals have an greater response to amphetamine than controls and that their baseline level of locomotor activity is higher than in controls during the light phase of the circadian cycle. Moreover, we have established that they have a strikingly higher startle response to acoustic stimulus and that this exaggerated response is normalized by treatment with the antidepressant desipramine. This normalization of the startle response is dependent on the normalization of the glucocorticoid receptor levels rather that the level of the circulating hormone itself. We already know that a similar treatment normalizes the glucocorticoid receptor mRNA levels in this transgenic model. Recent preliminary data indicate that these animals bear a reduced level of 5-HT2a receptor mRNA in the frontal cortex and that this abnormality is also corrected by antidepressant treatment. We have also established that these animals become sensitized to acoustic startle while controls do not. We think that this phenomenon might be related to a decreased level of NPY observed in the arcuate nucleus of the hypothalamus of these animals. Moreover, we have demonstrated that the desipramine treatment increases the levels of NPY in the amygdaloid complex where it is known to have an anxiolytic effect via its action in the central nucleus in particular.